Glucagon is a straight chain peptide hormone having 29 amino acids, which is secreted from pancreatic α cells and promotes glycogenolysis and gluconeogenesis in the liver. Diabetes patients generally show promoted secretion and reactivity of glucagon, which is one cause of hyperglycemia. Therefore, glucagon receptor antagonists can suppress excess sugar production from the liver by shutting off the actions of glucagon, and are expected to be therapeutic drugs for diabetes.
As glucagon antagonists, the following compounds are known.
1) a compound represented by the following formula:
wherein ring A is 6- to 10-membered aryl, 6- to 10-membered heteroaryl, 6-membered aryl condensed with 5- or 6-membered carbocycle; R1 is, when it is present, (a) halogen, OH, CO2R4, SOpR5, CN, NO2, C(O)NR6R7 or NR6R7, (b) C1-6 alkyl, C(O)C1-6 alkyl or C(O)C1-6 alkyl (substitutable with (a)), (c) 6- to 10-membered aryl, aryloxy or arylthio, or 5- to 10-membered heteroaryl, heteroaryl-oxy or heteroaryl-thio (each substitutable with (a) or (b); these groups are further substitutable with pyrazole, imidazole, tetrazole, pyrrole, triazole, thiazole, furan, thiophene, thiadiazole or oxazole (each substitutable with (a) or (b))); R2 is H, or substituent (a) or (b); X is —O—, —S—, —(C(R3)2)1-2—, —OC(R3)2— or —C(R3)2O—; R3 is H, or C1-10 alkyl, C2-4 alkenyl, aryl or heteroaryl (substitutable with (a) or (b); one of R3 is other than H or C1-10 alkyl); R4 is H or C1-6 alkyl; R5 is C1-10 alkyl, aryl or aryl-C1-10 alkyl; R6 and R7 are each H or C1-3 alkyl; p is 0-2; Ra is CH2CH2CO2R4, CH2CH(OH)CO2R4 or 5-tetrazole; and Rb is H, or substituent (a) or (b) (patent document 1: WO2006/102067).2) A compound represented by the following formula:
wherein R1 is (a) C1-10 alkyl, C2-10 alkenyl or C2-10 alkynyl (each substitutable), or (b) aryl, heteroaryl or heterocyclyl (each substitutable); R2 is H or R1; R3 and R4 are each H or C1-10 alkyl; R5 is H or F; R6 is H, OH, F or C1-3 alkyl, or R5 and R6 form oxo; R6 is H, or C1-10 alkyl (substitutable with phenyl, OH, OC1-6 alkyl, CO2H, CO2C1-6 alkyl, halo); m is 0-2; n is 1-6; when one of m and n is other than 0, Z is COR8, 5-tetrazolyl or 5-(2-oxo-1,3,4-oxadiazolyl), and when m and n are both 0, Z is 5-tetrazolyl or 5-(2-oxo-1,3,4-oxadiazolyl) (patent document 2: WO2004/069158).3) A compound represented by the following formula:
wherein V is —C(O)OR2, —C(O)NR2R3, —C(O)NR2OR3, —S(O)2OR2,
R2 and R3 are each independently H or C1-6 alkyl; R4 is H, halogen and the like; A is
b is 0 or 1; n is 0-3; R7 is H, C1-6 alkyl and the like; R8 and R9 are each independently H or C1-6 alkyl; Y is —C(O)—, —S(O)2—, —O— or a bond; Z is phenyl, 5-6-membered aromatic heterocycle (each substitutable with halo etc.); R1 is H or C1-6 alkyl; X is
r is 0 or 1; q and s are each 0-3; R12, R13, R14 and R15 are each independently H or C1-6 alkyl; D is
W is —O—, —S—, —S(O)2— or —NR20—; W′ is ═CR20′— or —N═; R16, R17, R18 and R19 are each independently H, —C(O)NR21R22, C(O)R21 and the like; R20 and R20′ are each H, C1-6 alkyl, C3-8 cycloalkyl or C3-8 cycloalkyl-C1-6 alkyl; R21 and R22 are each H, —CF3, C1-6 alkyl, aryl, heteroaryl and the like; and E is an optionally substituted 3- to 9-membered monocyclic or bicyclic ring and the like (patent document 3: WO00/69810).4) A compound represented by the following formula:
wherein A is
X is a bond, —CR1R2— or —NR1—; Y is >CR3— or >N—; R1, R2 and R3 are each independently H or C1-6 alkyl, or R1 and R2 optionally form a double bond; E is C1-10 alkyl, or C3-10 cycloalkyl, C3-10 cycloalkyl-C1-6 alkyl, aryl, heteroaryl or aryl-C1-6 alkyl (these are each substitutable with halogen, C1-6 alkyl etc.) and the like; B is
X′ is —N═ or —CR8═; Y′ is —S—, —O— or NR8—; R8 is H, or C1-6 alkyl or aryl (these are each substitutable with halogen, C1-6 alkyl etc.); R9 is H or C1-6 alkyl; D is aryl or heteroaryl (each substitutable with halogen, C1-10 alkyl, C1-6 alkoxy, C3-8 cycloalkyl, aryl (these rings are substitutable with halogen, C1-10 alkyl etc.) and the like) (patent document 4: WO2004/002480).
In addition, as a compound having a structure similar to that of the compound of the present invention, the following compound is known.
5) A compound useful as a therapeutic agent for inflammatory diseases, which is represented by the following formula
wherein G is phenyl or pyridyl; W is —NH(C═O) (CHR8)r—, —CH(R8)NH—, —NHCH(R8)—, —CH2—O— or —(C═O)O—; R8 is H or alkyl; r is 0, 1 or 2; R1 is H, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl and the like; R2 is H, optionally substituted alkyl, optionally substituted alkoxy, amino and the like; R3 is H, —CF3, —OCF3, halogen, optionally substituted C1-4 alkyl, —OR11 and the like; R4 is H, optionally substituted C1-4 alkyl, halogen, —CF3, —OCF3, —OR13 and the like; R5 is —CF3, —OCF3, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR13, —C(═O)R13, —C(═O)NR13R14 and the like; X is —(C═O)NH—, —NH(C═O)—, —NH(C═O)O—, —SO2NH—, —CO2— or a bond; R6 is H, optionally substituted C1-4 alkyl, optionally substituted alkoxy, optionally substituted phenoxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl and the like; R6 and R5 may be bonded to each other to form 5- or 6-membered ring; R11, R13 and R14 are each independently H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; m is 0, 1, 2 or 3 (patent document 5: WO2004/098528).    patent document 1: WO2006/102067    patent document 2: WO2004/069156    patent document 3: WO00/69610    patent document 4: WO2004/002480    patent document 5: WO2004/098528